D‐amino acids are being recognized as functionally important molecules in mammals. We recently identified endogenous D‐cysteine in mammalian brain. D‐cysteine is present in neonatal brain in substantial amounts (mM) and decreases with postnatal development. D‐cysteine binds to MARCKS and a host of proteins implicated in cell division and neurodevelopmental disorders. D‐cysteine decreases phosphorylation of MARCKS in neural progenitor cells (NPCs) affecting its translocation. D‐cysteine controls NPC proliferation by inhibiting AKT signaling. Exogenous D‐cysteine inhibits AKT phosphorylation at Thr 308 (...) and Ser 473 in NPCs. D‐cysteine treatment of NPCs led to 50% reduction in phosphorylation of Foxo1 at Ser 256 and Foxo3a at Ser 253. We hypothesize that in the developing brain endogenous D‐cysteine is as a physiologic regulator of NPC proliferation by inhibiting AKT signaling mediated by Foxo1 and Foxo3a. Endogenous D‐cysteine may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer's disease (AD). (shrink)

Recent research highlights that inflammatory signaling pathways such as pattern recognition receptor (PRR) signaling and inflammatory cytokine signaling play an important role in both on‐demand hematopoiesis as well as steady‐state hematopoiesis. Knockout studies have demonstrated the necessity of several distinct pathways in these processes, but often lack information about the contribution of specific cell types to the phenotypes in question. Transplantation studies have increased the resolution to the level of specific cell types by testing the necessity of inflammatory pathways specifically (...) in donor hematopoietic stem and progenitor cells (HSPCs) or in recipient niche cells. Here, we argue that for an integrated understanding of how these processes occur in vivo and to inform the development of therapies that modulate hematopoietic responses, we need studies that knockout inflammatory signaling receptors in a cell‐specific manner and compare the phenotypes caused by knockout in individual niche cells versus HSPCs. (shrink)

This paper discusses the evidence for the role of CREB in neural stem/progenitor cell (NSPC) function and oncogenesis and how these functions may be important for the development and growth of brain tumours. The cyclic‐AMP response element binding (CREB) protein has many roles in neurons, ranging from neuronal survival to higher order brain functions such as memory and drug addiction behaviours. Recent studies have revealed that CREB also has a role in NSPC survival, differentiation and proliferation. Recent work has (...) shown that over‐expression of CREB in transgenic animals can impart oncogenic properties on cells in various tissues and that aberrant CREB expression is associated with tumours in patients. It is the central position of CREB, downstream of key developmental and growth signalling pathways, which give CREB the ability to influence a spectrum of cell activities, such as cell survival, growth and differentiation in both normal and cancer cells. (shrink)

Experiments have suggested that umbilical cord blood stem cells can be used to prevent diseases such as atherosclerosis. This paper discusses ethical issues surrounding such usage such as the uncertainty that individuals at risk of a disease will actually get the disease; issues related to research with children; safety issues; from where these stem cells would be obtained; and whether these usages should be considered as therapies or as physical enhancements.

It has recently been shown that stem and progenitor cells undergo population self‐renewal to maintain epithelial homeostasis. The fate of individual cells is stochastic but the production of proliferating and differentiating cells is balanced across the population. This new paradigm, originating in mouse epidermis and since extended to mouse oesophagus and mouse and Drosophila intestine, is in contrast to the long held model of epithelial maintenance by exclusively asymmetric division of stem cells. Recent lineage tracing (...) studies have now shown that wound responses vary between tissues, and that a stem cell reserve is not essential as cycling progenitors and even differentiating cells contribute to regeneration. (shrink)

The liver progenitor cell (LPC) has enormous potential for use in cell therapy to treat liver disease. Since liver regenerates readily from pre‐existing hepatocytes, a role for LPCs and, indeed, their existence have been questioned. Research during the last decade has established that LPCs are an important alternative source of cells for liver regeneration. Their utility for cell therapy lies in their ability to generate both hepatocytes and cholangiocytes. However, they are observed in liver diseases that often lead (...) to cancer and there is experimental evidence that implicates LPCs as the source of tumours. This article provides a brief history of the studies that established the functional importance of LPCs in liver disease. It focuses on mouse models that have led to the identification of factors that regulate LPC growth and differentiation and discusses LPCs derived from different sources. Recent promising results from both in vitro and vivo studies suggest that LPCs could be useful for cell therapy. In the context of liver disease, LPCs may indeed be the cell of the future and understandably “our favourite cell”. BioEssays 27:1192–1202, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

An emerging concept is that quiescent mature skeletal cells provide an important cellular source for bone regeneration. It has long been considered that a small number of resident skeletal stem cells are solely responsible for the remarkable regenerative capacity of adult bones. However, recent in vivo lineage‐tracing studies suggest that all stages of skeletal lineage cells, including dormant pre‐adipocyte‐like stromal cells in the marrow, osteoblast precursor cells on the bone surface and other stem and (...) class='Hi'>progenitor cells, are concomitantly recruited to the injury site and collectively participate in regeneration of the damaged skeletal structure. Lineage plasticity appears to play an important role in this process, by which mature skeletal cells can transform their identities into skeletal stem cell‐like cells in response to injury. These highly malleable, long‐living mature skeletal cells, readily available throughout postnatal life, might represent an ideal cellular resource that can be exploited for regenerative medicine. (shrink)

The purpose of this essay is to stimulate academic discussion about the ethical justification of using human primordial stem cells for tissue transplantation, cell replacement, and gene therapy. There are intriguing alternatives to using embryos obtained from elective abortions and in vitro fertilisation to reconstitute damaged or dysfunctional human organs. These include the expansion and transplantation of latent adult progenitor cells.

Drosophila neural progenitor cells, or neuroblasts, alter their transcriptional profile over time to produce different neural cell types. A recent paper by Pearson and Doe shows that older neuroblasts can be reprogrammed to behave like young neuroblasts, and to produce early neural cell types, simply by expressing the transcription factor, Hunchback.1 The authors show that competence to respond to Hunchback diminishes over time. Mani pulating neural progenitors in this way may have important implications for therapeutic uses of neural (...) stem cells. BioEssays 26:711–714, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

In recent years, live imaging has been adopted to study stem cells in their native environment at cellular resolution. In the skeletal muscle field, this has led to visualising the initial events of muscle repair in mouse, and the entire regenerative response in zebrafish. Here, we review recent discoveries in this field obtained from live imaging studies. Tracking of tissue resident stem cells, the satellite cells, following injury has captured the morphogenetic dynamics of stem/progenitor cells (...) as they facilitate repair. Asymmetric satellite cell division generated a clonogenic progenitor pool, providing in vivo validation for this mechanism. Furthermore, there is an emerging role of stem/progenitor cell guidance at the injury site by cellular protrusions. This review concludes that live imaging is a critical tool for discovering the distinct processes that occur during regeneration, emphasising the importance of imaging in diverse animal models to capture the entire scope of stem cell functions. (shrink)

Clinical success with human hematopoietic stem cell (HSC) transplantation establishes a paradigm for regenerative therapies with other types of stem cells. However, it remains generally challenging to therapeutically treat tissues after engineering of stem cells in vitro. Recent studies suggest that stem and progenitor cells sense physical features of their niches. Here, we review biophysical contributions to lineage decisions, maturation, and trafficking of blood and immune cells. Polarized cellular contractility and nuclear rheology are separately shown (...) to be functional markers of a hematopoietic hierarchy that predict the ability of a lineage to traffic in and out of the bone marrow niche. These biophysical determinants are regulated by a set of structural molecules, including cytoplasmic myosin‐II and nuclear lamins, which themselves are modulated by a diverse range of transcriptional and post‐translational mechanisms. Small molecules that target these mechanobiological circuits, along with novel bioengineering methods, could prove broadly useful in programming blood and immune cells for therapies ranging from blood transfusions to immune attack of tumors. (shrink)

Robust ex vivo expansion of umbilical cord blood (UCB) derived hematopoietic stem and progenitor cells (HSPCs) should enable the widespread use of UCB as a source of cells to treat hematologic and immune diseases. Novel approaches for HSPC expansion have recently been developed, setting the stage for the production of blood stem cell derived products that fulfill our current best known criteria of clinical relevance. Translating these technologies into clinical use requires bioengineering strategies to overcome challenges of (...) scale‐up, reproducibility, and product quality assurance. Clinical‐scale implementation should also define criteria and targets for cost‐effective cell manufacturing. As production strategies become more effective, new opportunities in the therapeutic use of ex vivo expanded hematopoietic cell products will emerge. Herein we examine key technological milestones that need to be met in order to move ex vivo expanded HSPC therapies from the bench‐top to the bedside in a robust and reliable manner. (shrink)

T cells, which are derived from hematopoietic stem cells (HSCs), are the most important components of adaptive immune system. Based on the expression of αβ and γδ receptors, T cells are mainly divided into αβ and γδ T cells. In the thymus, they share common progenitor cells, while undergoing a series of well‐characterized and different developmental processes. N6‐Methyladenosine (m6A), one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance (...) of function. Recently, we have demonstrated that the depletion of m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells through the regulation of Jag1/Notch2 signaling, but not αβ T cells, indicating a checkpoint role of ALKBH5 and m6A modification in the early development of γδ T cells. Based on previous studies, many key pathway molecules, which exert dominant roles in γδ T cell fate determination, have been identified as the targets regulated by m6A modification. In this review, we mainly summarize the potential regulation between m6A modification and these key signaling molecules in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development. (shrink)

The sophisticated function of the central nervous system (CNS) is largely supported by proper interactions between neural cells and blood vessels. Accumulating evidence has demonstrated that neurons and glial cells support the formation of blood vessels, which in turn, act as migratory scaffolds for these cell types. Neural progenitors are also involved in the regulation of blood vessel formation. This mutual interaction between neural cells and blood vessels is elegantly controlled by several chemokines, growth factors, extracellular matrix, (...) and adhesion molecules such as integrins. Recent research has revealed that newly migrating cell types along blood vessels repel other preexisting migrating cell types, causing them to detach from the blood vessels. In this review, we discuss vascular formation and cell migration, particularly during development. Moreover, we discuss how the crosstalk between blood vessels and neurons and glial cells could be related to neurodevelopmental disorders. (shrink)

Mapping the paths that stem and progenitor cells take en route to differentiate and elucidating the underlying molecular controls are key goals in developmental and stem cell biology. However, with population level analyses it is difficult − if not impossible − to define the transition states and lineage trajectory branch points within complex developmental lineages. Single‐cell RNA‐sequencing analysis can discriminate heterogeneity in a population of cells and even identify rare or transient intermediates. In this review, we propose (...) that using these data, one can infer the lineage trajectories of individual stem cells and identify putative branch points. Clonal lineage tracing of stem cells allows one to define the outcome of differentiation. Integrating these single cell‐based approaches provides a robust strategy for establishing and testing models of how an individual stem cell changes through time to differentiate and self‐renew. (shrink)

Recent years have witnessed an explosion of the single-cell biochemical toolbox including chromosome conformation capture -based methods that provide novel insights into chromatin spatial organization in individual cells. The observations made with these techniques revealed that topologically associating domains emerge from cell population averages and do not exist as static structures in individual cells. Stochastic nature of the genome folding is likely to be biologically relevant and may reflect the ability of chromatin fibers to adopt a number of (...) alternative configurations, some of which could be transiently stabilized and serve regulatory purposes. Single-cell Hi-C approaches provide an opportunity to analyze chromatin folding in rare cell types such as stem cells, tumor progenitors, oocytes, and totipotent cells, contributing to a deeper understanding of basic mechanisms in development and disease. Here, we review key findings of single-cell Hi-C and discuss possible biological reasons and consequences of the inferred dynamic chromatin spatial organization. Single-cell Hi-C expands the molecular biology toolbox for studies of chromatin structure in individual cells. This technique allows one to analyze cell-to-cell variability in TAD and loop structure, and to capture chromosome conformation in rare cell types such as oocytes, totipotent cells, and tumor progenitors. (shrink)

Cell‐based therapies for degenerative diseases of the musculature remain on the verge of feasibility. Myogenic cells are relatively abundant, accessible, and typically harbor significant proliferative potential ex vivo. However, their use for therapeutic intervention is limited due to several critical aspects of their complex biology. Recent insights based on mouse models have advanced our understanding of the molecular mechanisms controlling the function of myogenic progenitors significantly. Moreover, the discovery of atypical myogenic cell types with the ability to cross the (...) blood‐muscle barrier has opened exciting new therapeutic avenues. In this paper, we outline the major problems that are currently associated with the manipulation of myogenic cells and discuss promising strategies to overcome these obstacles. (shrink)

The YAP/TAZ family of transcriptional co‐activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB‐Hippo/MST‐Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal (...) signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST‐LATS or Src family kinase activity to modulate YAP/TAZ activity. (shrink)

The vertebrate heart comprises a variety of cell types, the majority of which are cardiomyocytes, smooth muscle and endothelial cells. Their origin is still an intriguing research topic and the question is whether these cells derive from a common or from multiple distinct progenitor cell(s). Three recent publications not only suggest the existence of a single progenitor cell that can give rise to cardiovascular lineages but additionally uncovered, at least in part, the molecular identity of such (...) a multipotent precursor cell.1-3 These findings constitute major progress in the quest for stem-cell therapies for cardiac diseases. BioEssays 29:422–426, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The origin of insulin‐expressing β‐cells in the adult mammalian pancreas is controversial. During normal tissue turnover and following injury, β‐cells may be replaced by duplication of existing β‐cells.1 However, an alternative source of β‐cells has recently been proposed based on neogenesis from a Ngn3‐positive population present in regenerating pancreatic ducts.2 The appearance of β‐cells from Ngn3‐positive progenitors is reminiscent of normal pancreas development, and Ngn3‐expressing cells isolated from regenerating pancreas can generate the full repertoire (...) of endocrine phenotypes. The isolation and characterisation of the equivalent human progenitors may represent a significant step forward in the hunt for a cure for diabetes. BioEssays 30:617–620, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

During gestation, fetomaternal exchange occurs in the villous tree (labyrinth) of the placenta. Development of this structure depends on tightly coordinated cellular processes of branching morphogenesis and differentiation of specialized trophoblast cells. The basal chorionic trophoblast (BCT) cell layer that localizes next to the chorioallantoic interface is of critical importance for labyrinth morphogenesis in rodents. Gcm1‐positive cell clusters within this layer initiate branching morphogenesis thereby guiding allantoic fetal blood vessels towards maternal blood sinuses. Later these cells differentiate and (...) contribute to the syncytiotrophoblast of the fetomaternal barrier. Additional cells within the BCT layer sustain continued morphogenesis, possibly through a repopulating progenitor population. Several mouse mutants highlight the importance of a structurally intact BCT epithelium, and a growing number of studies addresses its patterning and epithelial architecture. Here, we review and discuss emerging concepts in labyrinth development focussing on the biology of the BCT cell layer. (shrink)

Stem cell self renewal, maintenance and differentiation are influenced by the convergence of intrinsic cellular signals and extrinsic microenvironmental cues from the surrounding stem cell niche. However, the specific signals involved are often still poorly understood. This is also true for skin epithelial stem cells. Recently, by transcriptionally profiling of embryonic hair progenitors in mice, Rhee et al.1 have managed to define how murine hair follicle epithelial stem cells are specified and maintained in an undifferentiated state. These authors (...) have identified Lhx2 as a transcription factor functionally positioned downstream of signals necessary to specify hair follicle stem cells such as p63 or NFκB, but upstream of signals like Wnt/β‐catenin, Bmp or Shh that are required to drive activated stem cells via the production of transient amplifying cells into terminal differentiation. BioEssays 28: 1157–1160, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Establishment of cell lineage identity from multipotent progenitors is controlled by cooperative actions of lineage‐specific and stably expressed transcription factors, combined with input from environmental signals. Lineage‐specific master transcription factors activate and repress gene expression by recruiting consistently expressed transcription factors and chromatin modifiers to their target loci. Recent technical advances in genome‐wide and multi‐omics analysis have shed light on unexpected mechanisms that underlie more complicated actions of transcription factors in cell fate decisions. In this review, we discuss functional dynamics (...) of stably expressed and continuously required factors, Notch and Runx family members, throughout developmental stages of early T cell development in the thymus. Pre‐ and post‐commitment stage‐specific transcription factors induce dynamic redeployment of Notch and Runx binding genomic regions. Thus, together with stage‐specific transcription factors, shared transcription factors across distinct developmental stages regulate acquisition of T lineage identity. (shrink)

Neural crest cells are multipotent progenitors, capable of producing diverse cell types upon differentiation. Recent studies have identified significant heterogeneity in both the fates produced and genes expressed by different premigratory crest cells. While these cells may be specified toward particular fates prior to migration, transplant studies show that some may still be capable of respecification at this time. Here we summarize evidence that extracellular signals in the local environment may act to specify premigratory crest and thus (...) generate diversity in the population. Three main classes of signals–Wnts, BMP2/BMP4 and TGFβ1,2,3–have been shown to directly influence the production of particular neural crest cell fates, and all are expressed near the premigratory crest. This system may therefore provide a good model for integration of multiple signaling pathways during embryonic cell fate specification. BioEssays 22:708–716, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Development and homeostasis of the haematopoietic system is dependent upon stem cells that have the unique ability to both self‐renew and to differentiate in all cell lineages of the blood. The crucial decision between haematopoietic stem cell (HSC) self‐renewal and differentiation must be tightly controlled. Ultimately, this choice is regulated by the integration of intrinsic signals together with extrinsic cues provided by an exclusive microenvironment, the so‐called haematopoietic niche. Although the haematopoietic system of vertebrates has been studied extensively for (...) many decades, the specification of the HSC niche and its signals involved are poorly understood. Much of our current knowledge of how niches regulate long‐term maintenance of stem cells is derived from studies on Drosophila germ cells. Now, two recently published studies by Mandal et al.1 and Krezmien et al.2 describe the Drosophila haematopoietic niche and signal transduction pathways that are involved in the maintenance of haematopoietic precursors. Both reports emphasize several features that are important for controlling stem cell behavior and show parallels to both the vertebrate haematopoietic niche as well as the Drosophila germline stem cell niches in ovary and testis. The findings of both papers shed new light on the specific interactions between haematopoietic progenitors and their microenvironment. BioEssays 29:713–716, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Neural crest cells are multipotent progenitors, capable of producing diverse cell types upon differentiation. Recent studies have identified significant heterogeneity in both the fates produced and genes expressed by different premigratory crest cells. While these cells may be specified toward particular fates prior to migration, transplant studies show that some may still be capable of respecification at this time. Here we summarize evidence that extracellular signals in the local environment may act to specify premigratory crest and thus (...) generate diversity in the population. Three main classes of signals–Wnts, BMP2/BMP4 and TGFβ1,2,3–have been shown to directly influence the production of particular neural crest cell fates, and all are expressed near the premigratory crest. This system may therefore provide a good model for integration of multiple signaling pathways during embryonic cell fate specification. BioEssays 22:708–716, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Recent studies support a model in which the progeny of SOX9+ epithelial progenitors at the distal tip of lung branches undergo cell allocation and differentiation sequentially along the distal‐to‐proximal axis. Concomitant with the elongation and ramification of lung branches, the descendants of the distal SOX9+ progenitors are distributed proximally, express SOX2, and differentiate into cell types in the conducting airways. Amid subsequent sacculation, the distal SOX9+ progenitors generate alveolar epithelial cells to form alveoli. Sequential cell allocation and differentiation are (...) integrated with the branching process to generate a functional branching organ. This review focuses on the roles of SOX9+ cells as precursors for new branches, as the source of various cell types in the conducting airways, and as progenitors of the alveolar epithelium. All of these processes are controlled by multiple signaling pathways. Many mouse mutants with defective lung branching contain underlying defects in one or more steps of cell allocation and differentiation of SOX9+ progenitors. This model provides a framework to understand the molecular basis of lung phenotypes and to elucidate the molecular mechanisms of lung patterning. It builds a foundation on which comparing and contrasting the mechanisms employed by different branching organs in diverse species can be made. (shrink)

Skin pigment pattern formation is a paradigmatic example of pattern formation. In zebrafish, the adult body stripes are generated by coordinated rearrangement of three distinct pigment cell‐types, black melanocytes, shiny iridophores and yellow xanthophores. A stem cell origin of melanocytes and iridophores has been proposed although the potency of those stem cells has remained unclear. Xanthophores, however, seemed to originate predominantly from proliferation of embryonic xanthophores. Now, data from Singh et al. shows that all three cell‐types derive from shared (...) stem cells, and that these cells generate peripheral neural cell‐types too. Furthermore, clonal compositions are best explained by a progressive fate restriction model generating the individual cell‐types. The numbers of adult pigment stem cells associated with the dorsal root ganglia remain low, but progenitor numbers increase significantly during larval development up to metamorphosis, likely via production of partially restricted progenitors on the spinal nerves. (shrink)

The transcription factor Pax5 is essential for the initial commitment of hematopoietic progenitors to the B cell lineage. Recently, our understanding of the lineage commitment process has been extended with the finding that Pax5 is also continuously required throughout B cell development to reinforce commitment, as inactivation of Pax5 in mature B cells results in their de‐differentiation to a progenitor stage that is capable of multi‐lineage potential.1 The reliance of B cell identity on a single gene is not (...) without its problems as the loss of Pax5 results in B cell malignancies in mouse models and mutation in human PAX5 is the most‐common genetic lesion in acute lymphoblastic leukemia. BioEssays 30:203–207, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Transposable elements (TEs) have emerged as important factors in establishing the cell type‐specific gene regulatory networks and evolutionary novelty of embryonic and placental development. Recently, studies on the role of TEs and their dysregulation in cancers have shed light on the transcriptional, transpositional, and regulatory activity of TEs, revealing that the activation of developmental transcriptional programs by TEs may have a role in the dedifferentiation of cancer cells to the progenitor‐like cell states. This essay reviews the recent evidence (...) of the cis‐regulatory TEs (henceforth crTE) in normal development and malignancy as well as the key transcription factors and regulatory pathways that are implicated in both cell states, and presents existing gaps remaining to be studied, limitations of current technologies, and therapeutic possibilities. (shrink)

Despite decades of research, remaining safety concerns regarding disease transmission, heterotopic tissue formation, and tumorigenicity have kept stem cell‐based therapies largely outside the standard‐of‐care for musculoskeletal medicine. Recent insights into trophic and immune regulatory activities of mesenchymal stem cells (MSCs), although incomplete, have stimulated a plethora of new clinical trials for indications far beyond simply supplying progenitors to replenish or re‐build lost/damaged tissues. Cell banks are being established and cell‐based products are in active clinical trials. Moreover, significant advances have (...) also been made in the field of pluripotent stem cells, in particular the recent development of induced pluripotent stem cells. Their indefinite proliferation potential promises to overcome the limited supply of tissue‐specific cells and adult stem cells. However, substantial hurdles related to their safety must be overcome for these cells to be clinically applicable. (shrink)

The study of haemopoiesis enables us to address one of the central questions of developmental biology, concerning the molecular mechanisms by which a multipotent cell develops into distinct differentiated progeny. Recent work(1) suggests specific roles for retinoic acid receptors at two distinct stages of haemopoiesis. Continuous cell lines of lymphohaemopoietic progenitors were established by infection with a retrovirus containing a dominant negative retinoic acid receptor. The cell lines depend on stem cell factor for their proliferation and can be induced to (...) diffentiate into B‐lymphocytes, erythrocytes, neutrophils, monocytes, mast cells and megakaryocytes. Since lymphohaemopoietic progenitors represent less than 0.01% of nucleated marrow cells, immortalised progenitors provide a valuable system with which to study haemopoiesis on a molecular level. (shrink)

Clonal disease is often regarded as almost synonymous with cancer. However, it is becoming increasingly clear that our bodies harbor numerous mutant clones that are not tumors, and mostly give rise to no disease at all. Here we discuss three somatic mutations arising within the hematopoietic system: BCR‐ABL, characteristic of chronic myeloid leukemia; mutations of the PIG‐A gene, characteristic of paroxysmal nocturnal hemoglobinuria; the V617F mutation in the JAK2 gene, characteristic of myeloproliferative diseases. The population frequencies of these three blood (...) disorders fit well with a hierarchical model of hematopoiesis. The fate of any mutant clone will depend on the target cell and on the fitness advantage, if any, that the mutation confers on the cell. In general, we can expect that only a mutation in a hematopoietic stem cell will give long‐term disease; the same mutation taking place in a cell located more downstream may produce just a ripple in the hematopoietic ocean. (shrink)

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) is a nuclear protein that plays a crucial role in various biological functions, such as RNA splicing and chromatin organization. HNRNPU/scaffold attachment factor A (SAF‐A) activities are essential for regulating gene expression, DNA replication, genome integrity, and mitotic fidelity. These functions are critical to ensure the robustness of developmental processes, particularly those involved in shaping the human brain. As a result, HNRNPU is associated with various neurodevelopmental disorders (HNRNPU‐related neurodevelopmental disorder, HNRNPU‐NDD) characterized by developmental delay (...) and intellectual disability. Our research demonstrates that the loss of HNRNPU function results in the death of both neural progenitor cells and post‐mitotic neurons, with a higher sensitivity observed in the former. We reported that HNRNPU truncation leads to the dysregulation of gene expression and alternative splicing of genes that converge on several signaling pathways, some of which are likely to be involved in the pathology of HNRNPU‐related NDD. (shrink)

The cerebral cortex controls our most distinguishing higher cognitive functions. Human‐specific gene expression differences are abundant in the cerebral cortex, yet we have only begun to understand how these variations impact brain function. This review discusses the current evidence linking non‐coding regulatory DNA changes, including enhancers, with neocortical evolution. Functional interrogation using animal models reveals converging roles for our genome in key aspects of cortical development including progenitor cell cycle and neuronal signaling. New technologies, including iPS cells and (...) organoids, offer potential alternatives to modeling evolutionary modifications in a relevant species context. Several diseases rooted in the cerebral cortex uniquely manifest in humans compared to other primates, thus highlighting the importance of understanding human brain differences. Future studies of regulatory loci, including those implicated in disease, will collectively help elucidate key cellular and genetic mechanisms underlying our distinguishing cognitive traits. (shrink)

The ontogeny of the vertebrate retina has been a topic of interest to developmental biologists and human geneticists for many decades. Understanding the unfolding of the genetic program that transforms a field of progenitors cells into a functionally complex and multi‐layered sensory organ is a formidable challenge. Although classical genetic studies succeeded in identifying the key regulators of retina specification, understanding the architecture of their gene network and predicting their behavior are still a distant hope. The emergence of next‐generation (...) sequencing platforms revolutionized the field unlocking the access to genome‐wide datasets. Emerging techniques such as RNA‐seq, ChIP‐seq, ATAC‐seq, or single cell RNA‐seq are used to characterize eye developmental programs. These studies provide valuable information on the transcriptional and cis‐regulatory profiles of precursors and differentiated cells, outlining the trajectories that connect each intermediate state. Here, recent systems biology efforts are reviewed to understand the genetic programs shaping the vertebrate retina. (shrink)

Many recent gene knockout experiments cause anatomical changes to the jaw region of mice that several investigators claim are evolutionary reversals. Here we evaluate these mutant phenotypes and the assertions of atavism. We argue that following the knockout of Hoxa-2, Dlx-2, MHox, Otx2, and RAR genes, ectopic cartilages arise as secondary consequences of disruptions in normal processes of cell specification, migration, or differentiation. These disruptions cause an excess of mesenchyme to accumulate in a region through which skeletal progenitor (...) class='Hi'>cells usually migrate, and at a site of condensation that is normally present in mammals but that is too small to chondrify. We find little evidence that these genes, when disrupted, cause a reversion to any primitive condition and although changes in their expression may have played a role in the evolution of the mammalian jaw, their function during morphogenesis is not sufficiently understood to confirm such hypotheses. BioEssays 20:245–255, 1998.© 1998 John Wiley & Sons, Inc. (shrink)

Classical mutations at the mouse Brachyury (T) locus were discovered because they lead to shortened tails in heterozygous newborns. no tail (ntl) mutants in the zebrafish, as their name suggests, show a similar phenotype. In Drosophila, mutants in the brachyenteron (byn) gene disrupt hindgut formation. These genes all encode T-box proteins, a class of sequence-specific DNA binding proteins and transcription factors. Mutations in the C. elegans mab-9 gene cause massive defects in the male tail because of failed fate decisions in (...) two tail progenitor cells. In a recent paper, Woollard and Hodgkin1 have cloned the mab-9 gene and found that it too encodes a T-box protein, similar to Brachyury in vertebrates and brachyenteron in Drosophila. The authors suggest that their results support models for an evolutionarily ancient role for these genes in hindgut formation. We will discuss this proposal and try to decide whether the gene sequences, gene interactions and gene expression patterns allow any conclusions to be made about the rear end of the ancestral metazoan. BioEssays 22:781–785, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Various cell types cooperate to create a highly organized and dynamic micro-environmental niche in the bone marrow. Over the past several years, the field has increasingly recognized the critical roles of the interplay between bone marrow environment and hematopoietic cells in normal and deranged hematopoiesis. These advances rely on several new technologies that have allowed us to characterize the identity and roles of these niches in great detail. Here, we review the progress of the last several years, list some (...) of the outstanding questions in the field and propose ways to target the diseased environment to better treat hematologic diseases. Understanding the extrinsic regulation by the niche will help boost hematopoiesis for regenerative medicine. Based on natural development of hematologic malignancies, we propose that combinatory targeting the niche and hematopoietic intrinsic mechanisms in early stages of hematopoietic malignancies may help eliminate minimal residual disease and have the highest efficacy. The bone marrow is the home for blood-forming hematopoietic stem and progenitor cells. Normal generation of blood and immune cells depends on highly regulated interactions between these stem and progenitor cells with their surrounding environment. Emerging evidence suggests that therapeutic interventions directed at these cellular interdependencies can help boost hematopoiesis and eradicate malignant hematopoietic cells. (shrink)

Hippocampal neurogenesis has been implicated in the pathogenesis of and recovery from depression. However, most of the underlying studies were endpoint investigations in experimental animals yielding conflicting results, and it has been under debate to which extent these results could be transferred to human patients. Now, researchers have developed a powerful new tool to address these questions by a non‐invasive method in humans and animals in vivo, using magnetic resonance spectroscopy to detect a biomarker for proliferating progenitor cells (...) that give rise to new neurons.1 This makes it possible to study the role of neural progenitor cells in a wide variety of human brain disorders. BioEssays 30:806–810, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Embryonic development combines paradoxical properties: it has great precision, it is usually conducted at breakneck speed and it is flexible on relatively short evolutionary time scales, particularly at early stages. While these features appear mutually exclusive, we consider how they may be reconciled by the properties of key early regulatory networks. We illustrate these ideas with the network that controls development of endoderm progenitors. We argue that this network enables precision because of its intrinsic stability, self propagation and dependence on (...) signalling. The network enables high developmental speed because it is rapidly established by maternal inputs at multiple points. In turn these properties confer flexibility on an evolutionary time scale because they can be initiated in many ways, while buffering essential progenitor cell populations against changes in their embryonic environment on both evolutionary and developmental time scales. Although stable, these networks must be capable of rapid dissolution as cell differentiation progresses. While we focus on the core early endodermal network of vertebrates, we argue that these properties are likely to be general in early embryonic stem cell populations, such as mammalian ES cells. BioEssays 30:757–765, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Mutations in the CEBPA gene are present in 10–15% of acute myeloid leukemia (AML) patients. The most frequent type of mutations leads to the expression of an N‐terminally truncated variant of the transcription factor CCAAT/enhancer‐binding protein alpha (C/EBPα), termed p30. While initial reports proposed that p30 represents a dominant‐negative version of the wild‐type C/EBPα protein, other studies show that p30 retains the capacity to actively regulate gene expression. Recent global transcriptomic and epigenomic analyses have advanced the understanding of the distinct (...) roles of the p30 isoform in leukemogenesis. This review outlines direct and indirect effects of the C/EBPα p30 variant on oncogenic transformation of hematopoietic progenitor cells and discusses how studies of N‐terminal CEBPA mutations in AML can be extrapolated to identify novel gain‐of‐function features in oncoproteins that arise from recurrent truncating mutations in transcription factors. (shrink)

The size and organization of the brain are determined by the activity of progenitor cells early in development. Key mechanisms regulating progenitor cell biology involve miRNAs. These small noncoding RNA molecules bind mRNAs with high specificity, controlling their abundance and expression. The role of miRNAs in brain development has been studied extensively, but their involvement at early stages remained unknown until recently. Here, recent findings showing the important role of miRNAs in the earliest phases of brain development (...) are reviewed, and it is discussed how loss of specific miRNAs leads to pathological conditions, particularly adult and pediatric brain tumors. Let‐7 miRNA downregulation and the initiation of embryonal tumors with multilayered rosettes (ETMR), a novel link recently discovered by the laboratory, are focused upon. Finally, it is discussed how miRNAs may be used for the diagnosis and therapeutic treatment of pediatric brain tumors, with the hope of improving the prognosis of these devastating diseases. (shrink)

New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. (...) These tumors may therefore be susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity. -/- . (shrink)

The recent finding that the human version of a neurodevelopmental enhancer of the Wnt receptor Frizzled 8 (FZD8) gene alters neural progenitor cell cycle timing and brain size is a step forward to understanding human brain evolution. The human brain is distinctive in terms of its cognitive abilities as well as its susceptibility to neurological disease. Identifying which of the millions of genomic changes that occurred during human evolution led to these and other uniquely human traits is extremely challenging. (...) Recent studies have demonstrated that many of the fastest evolving regions of the human genome function as gene regulatory enhancers during embryonic development and that the human‐specific mutations in them might alter expression patterns. However, elucidating molecular and cellular effects of sequence or expression pattern changes is a major obstacle to discovering the genetic bases of the evolution of our species. There is much work to do before human‐specific genetic and genomic changes are linked to complex human traits. (shrink)

The evolutionary history of muscle development in the paired fins of teleost fish and the limbs of tetrapod vertebrates is still, to a large extent, uncertain. There has been a consensus, however, that in the vertebrate clade the ancestral mechanism of fin and limb muscle development involves the extension of epithelial tissues from the somite into the fin/limb bud. This mechanism has been documented in chondrichthyan, dipnoan, chondrostean and teleost fishes. It has also been assumed that in amniotes, in contrast, (...) individual progenitor cells of muscles migrate from the somites into the limb buds. Neyt et al.(1) now present the exciting finding that in zebrafishes this presumably derived mechanism involving individual cell migration, is present. They conclude, based on data on sharks, zebrafishes, chickens, quails and mice that the derived mechanism was present in the sarcopterygians. This conclusion, however, may be premature in the light of further data available in the literature, which show a highly mosaic distribution of this character in the vertebrate clade. Furthermore, a developmental mode exists that is intermediate between the supposed ancestral and derived modes in teleosts, reptiles and possibly amphibians. BioEssays 23:383–387, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Platelet‐derived growth factor (PDGF) was originally identified in platelets and in serum as a mitogen for fibroblasts, smooth muscle cells (SMC) and glia cells in culture. PDGF has since expanded to a family of dimers of at least four gene products, whose biological actions are mediated through two receptor tyrosine kinases, PDGFRs. The present review summarizes and discusses the biological functions of PDGFs and PDGFRs in developmental processes, mainly as revealed through genetic analysis in mice. Such studies have (...) demonstrated multiple critical roles of PDGFs and PDGFRs in embryonic and postnatal development. PDGFs seem to act upon specific populations of progenitor cells that give rise to several different cell types with distinct functions in a variety of developmental processes. Analogies are seen between the cell functions and the developmental processes controlled by PDGFs. This suggests that ancestral PDGF and PDGFR expression patterns and functions may have been iterated in related sets of morphogenetic processes in the course of evolution. BioEssays 23:494–507, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

One of the earliest and most‐fundamental pattern‐ formation events in embryonic development is endoderm and mesoderm specification. In sea urchin embryos, this process begins with blimp1 and wnt8 gene expression at the vegetal pole as soon as embryonic transcription begins. Shortly afterwards, wnt8/blimp1 expression spreads to the adjacent ring of mesoderm progenitor cells and is extinguished in the vegetal‐most cells. A little later, the ring of wnt8/blimp1 activity moves out of the mesoderm progenitors and into the neighboring (...) endoderm cells. Remarkably, this moving ring of gene expression has now been shown to be controlled entirely by transcriptional cis‐regulatory logic.1. BioEssays 30:412–417, 2008. © 2008 Wiley Periodicals, Inc. (shrink)